PROJECT SUMMARY/ABSTRACT The long-term goal of this study is to identify valid targets and strategies for the prevention and treatment of obesity-related cardiovascular disease. Obesity is characterized by a large accumulation of fat tissues that secrete numerous inflammatory mediators (called adipocytokines), generating a systemic inflammatory state. These adipocytokines induce vascular dysfunction which is the initial step towards developing cardiovascular disease. Obesity is affected by environmental factors such as diet and physical activity. These factors induce epigenetic changes, which are changes that affect gene expression without altering the DNA sequence. One of these epigenetic modifications is the reduction in DNA methylation (referred to as hypomethylation) resulting in subsequent increases in gene expression. Our preliminary studies showed that the extracted DNA from fat tissues of obese subjects is hypomethylated compared to non-obese controls. DNA hypomethylation correlated significantly with higher expression of adipocytokines and impaired vasodilation in obese subjects. Therefore, we hypothesize that the increase in adipocytokine expression in obese adults is mediated by DNA hypomethylation and that DNA hypomethylation is a promising target to prevent obesity-associated inflammation and vascular dysfunction. The flexible modifiable nature of DNA methylation makes it a perfect target for life style interventions such as physical activity and weigh loss. Thus, we propose that aerobic exercise training and weight loss following Bariatric surgery will reverse DNA hypomethylation and improve vascular function in obese subjects. We will test our hypotheses by (1) Investigating abnormal DNA methylation patterns of adipocytokines in fat tissues from obese adults between the age of 18 and 50 compared to non-obese subjects; (2) Test the effectiveness of 12-week aerobic exercise training on reversing DNA hypomethylation and improving vascular function in obese adults; and (3) Examine the effectiveness of weight loss surgery on DNA methylation and vascular function. The proposed studies will improve our understanding of the epigenetic underpinning of obesity-related vascular dysfunction, identify novel therapeutic targets for improving vascular function in obese adults, and provide an evidence for the positive effects of aerobic exercise training and weight loss on the prevention and treatment of obesity-associated cardiovascular disease. These studies will have a positive impact on improving the prevention and therapeutic management of obesity-related cardiovascular morbidities that affect millions of people worldwide. Therefore, we propose a focused career development training plan during which the applicant will be trained in the responsible conduct of clinical research, learn all aspects of how to start, implement and manage a clinical study and how to lead a clinical research team, efficiently. By completing the proposed training (K99), the applicant will obtain the knowledge and skills that will provide the initial steps towards her scientific autonomy in the subsequent phase (R00) and she will be well positioned to transition successfully from the role of a postdoctoral trainee to that of an independent researcher.